Sequencing Study Highlights Genetic Diversity in Southern Africa

NEW YORK (GenomeWeb News) – An international research team reported in Nature today that it has characterized five human genomes from southern Africa, identifying millions of SNPs never before found in the human population.

The American, African, and Australian researchers sequenced the full genomes of two African individuals: a member of a hunter-gatherer population in the Kalahari desert known as the Bushmen, San, or Khoisan, and a Bantu individual from South Africa — Nobel peace prize winner Archbishop Desmond Tutu. After sequencing the exomes of three other Khoisan men, the team compared all five genomes, identifying more than 1.3 million previously undetected SNPs.

During their subsequent analyses, they not only found genetic differences between southern African populations and populations from other parts of Africa and the world but also within the Khoisan population — findings that may eventually inform everything from studies of human population history and adaptations to agriculture to personalized medicine strategies in southern Africa.

“On average, there are more genetic differences between any two Bushmen in our study than between a European and an Asian,” co-lead author Stephan Schuster, a biochemistry and molecular biology researcher with Pennsylvania State University’s Center for Comparative Genomics and Bioinformatics, said in a statement.

Southern Africa is believed to be the source of modern humans and, subsequently, is home to a great deal of human genetic diversity. But despite the decades-long effort to characterize the human genome and human population genetics, most studies have lacked representatives from this region, Schuster explained during a telephone briefing with reporters this morning.

In an effort to get a better sense of the genetic variation within humans, he and his team set out to characterize the genomes of individuals from the Khoisan population — thought to be the oldest modern human population. Schuster described the project at the American Society for Human Genetics meeting last fall, though this paper marks the first publication from the sequencing effort.

Archbishop Tutu, who has ancestry from Sotho-Tswana and Nguni language groups, which represent roughly 90 percent of southern Africans, also participated in the study. Tutu was a good candidate not only because of his ancestry but also because he is known to have survived polio, tuberculosis, and prostate cancer and because he is a voice for southern Africa and indigenous populations, senior author Vanessa Hayes, a cancer genetics researcher at the University of New South Wales, told reporters.

The four Khoisan men who participated in the study all came from different communities in Namibia’s Kalahari Desert. Each was the most elder member of his community.

The team sequenced the genome of a Khoisan man named named !Gubi to 10.2 times coverage using paired-end sequencing with the Roche 454 GS FLX Titanium platform. !Gubi is believed to be around 86 years old and lives in the southern Kalahari on the Namibia-Botswana border. They also used a similar approach to sequence the genome of a second Khoisan man named G/aq’o, from a community in the northern Kalahari, to about two times coverage.

For the exome sequencing portion of the study, the team captured protein-coding sequences for each of the five individuals with the NimbleGen 2.1 M array and sequenced them by Roche 454 Titanium sequencing.

The genomic and exomic sequences were verified using a range of approaches, including genotyping and whole-genome and exome sequencing with the Illumina platform, which was used to sequence !Gubi’s genome to 23.2 times coverage and Tutu’s genome to 7.2 times coverage.

When the team compared the genomes and exomes to version 18 of the human reference genome and eight personal genomes sequenced, they found 1.3 million previously undetected SNPs, including 13,146 new SNPs that alter the amino acid sequence of 7,720 genes.

!Gubi’s genome contained more SNPs than Tutu’s, though both contained more SNPs overall — and more novel SNPs — than any other individual genome sequenced so far.

And from their population level analyses, the researchers detected as many or more genetic differences between the Khoisan and West African populations than between West African and European populations.

The team’s preliminary peek at the functional role of genes affected by new SNPs in the Khoisan population suggests that these variants tend to fall in genes involved in immune response, reproduction, and sensory perception.

“We believed that because of their extremely long lineage, their genome would be very different,” co-lead author Webb Miller, a researcher at Penn State’s Center for Comparative Genomics and Bioinformatics, told reporters. And, he said, the findings so far support that hypothesis.

This type of genetic diversity within the human genome is believed to have helped humans thrive over thousands of years, Schuster said, though he emphasized that modern human genomes from all around the world still share far more similarities than differences. “We are genetically one healthy species,” he said.

The team believes understanding human genetic diversity in southern Africa will likely be medically important, both for developing personalized medicine in this region and for identifying and understanding the roles of rare variants in human health and disease in general.

“Adding the described variants to current databases will facilitate the inclusion of southern Africans in medical researchers’ efforts, particularly when family and medical histories can be correlated with genome-wide data,” the researchers wrote.

The researchers have already started developing microarrays incorporating the newly identified southern African SNPs. For the next phase of the study, they plan to use these microarrays to genotype hundreds of individuals from southern Africa.